Efficacy of Topiramate Alone and Topiramate Plus Vitamin D3 in the Prophylaxis of Pediatric Migraine: A Randomized Clinical Trial

Objective Topiramate is effective in the prevention of pediatric migraine, and studies show that vitamin D3 supplementation might also be useful in the treatment of adult migraineurs with a normal vitamin D3 level. The present study aimed at comparing the efficacy and safety of topiramate plus vitamin D3 and topiramate alone in the prophylaxis of pediatric migraine. Materials & Methods In a single-blinded, randomized, clinical trial, 5-15-year-old children with migraine headaches, referred to the Pediatric Neurology Clinic of Shahid Sadoughi Medical Sciences University, Yazd, Iran from January 2016 to January 2017, were randomly allocated to receive 2 mg/kg/day of topiramate or 2 mg/kg/day of topiramate plus one 500,000 IU vitamin D3 pearl weekly for two consecutive months. Primary outcomes were the reduction of monthly frequency, severity, duration, and the disability score of migraine, and the secondary outcomes included a good response to treatment (more than 50% reduction in monthly headache frequency) and a lack of clinical adverse events. Results Totally, 31 female and 26 male children with the mean age of 10.02±2.11 years were evaluated. Both drugs were effective in the reduction of monthly frequency, severity, duration, and disability for headaches. Nevertheless, the combination of topiramate and vitamin D3 was more effective than topiramate alone in reducing the monthly headaches frequency (6.12±1.26 vs. 9.87±2.44 times, P=0.01) and disability score (19.24±6.32 vs. 22.11±7.91, P=0.02). Good response to treatment was observed in 60.7% and 75.9% of the subjects in the topiramate alone and topiramate plus vitamin D3 groups, respectively, and topiramate plus vitaminD3 was more effective (P= 0.01). Transient mild side effects were observed in 14.3% and 17.2% of the subjects in the topiramate alone and topiramate plus vitamin D3 groups, respectively (P=0.8). Conclusion A combination of topiramate and vitamin D3 might be considered safe and more effective than topiramate alone in the prophylaxis of pediatric migraine.


Introduction
Migraine, as the most common primary headache in children, occurs in up to 10.6% of the 5-15-yearold children and migraine prophylaxis should be started if headache episodes occur more than once a week or the disability score is higher than 20 based on the pediatric migraine disability assessment scale (ped MIDAS) (1). There is no unique guideline for the prophylaxis of pediatric migraine, although the US Food and Drug Administration has approved flunarizine and, recently, topiramate for migraine prophylaxis in pediatric patients (2), and topiramate, as a safe and effective drug, should be strongly encouraged for migraine prevention in children (3).
Today, physicians are interested in using alternative medicine and non-pharmacological remedies for migraine prevention, and many nutraceutics, such as magnesium, coenzyme Q10, riboflavin, butterbur, feverfew, melatonin, etc., are utilized for the prophylaxis of migraine in children and adults (4).
Association between the dysfunction of transporter proteins of vitamin D 3 metabolites and migraine attacks was observed in a study by Nagata et al. (9), and that higher levels of vitamin D 3 might reduce the risk of migraine headaches. In some researches, patients with non-migraine headaches had low serum levels of 25-hydroxyvitamin D 3 (7,10,11). Association between migraine and serum 25-hydroxyvitamin D 3 level was not observed in some studies (10,12,13). However, in a study in Isfahan, Iran, a positive relationship was observed Iran J Child Neurol. Autumn 2020 Vol. 14 No. 4 between serum levels of vitamin D 3 and migraine (14), and in another study in Tehran, adult migraineurs had a lower serum vitamin D 3 level and vitamin D 3 deficiency, and insufficiency was more frequent in them compared to healthy controls. It was concluded that the increase in serum levels of 25-hydroxyvitamin D 3 might decrease the risk of migraine headaches (15). In a study in Turkey, serum vitamin D 3 level was lower in patients with migraine (16). Association between the prevalence of migraine and the latitude was observed, and the higher latitude had a higher one-year prevalence for migraine. Moreover, the presence of vitamin D receptor, 1alpha-hydroxylase, and vitamin D-binding protein in the hypothalamus was suggestive of the role of vitamin D 3 deficiency in the incidence of migraine headaches (17). The present study aimed at answering the question that whether or not topiramate plus vitamin D 3 is more efficient than topiramate alone in reducing the monthly frequency, severity, and the disability score in 5-15-year-old migraineur children without vitamin D 3 deficiency.

Materials & Methods
In a randomized, single-blind, clinical, openlabel, parallel-group study, the efficacy of topiramate alone and topiramate plus vitamin Totally, 60 children were randomly assigned to two groups to receive 2 mg/kg/day of topiramate or 2 mg/kg/day of topiramate plus one 500,000 IU vitamin D 3 pearl weekly for two consecutive months. In the current study, 500,000 IU vitamin days and, then, monthly frequency, severity, and duration of headaches, and the pedMIDAS scores before and after three months of intervention were compared. A more than 50% reduction in monthly headaches frequency was considered as a good response to treatment.
Primary outcomes were the frequency of good response to treatment (more than 50% reduction in monthly headaches frequency), and reduction in severity, duration, and disability for headaches.

Results
Two children in the topiramate alone and one in the topiramate plus vitamin D 3 groups discontinued drug usage during the follow-up period, and finally, the trial was completed with 57 children, 31 females (45.6%) and 26 males (54.4%), with the mean age of 10.02 ± 2.11 years.
The comparison of some characteristics of the children in both groups is shown in Table 1, indicating that age and gender distribution, as well as the type and positive family history of migraine, were not significantly different between the two groups. Table 2 shows the comparison of headaches characteristics before treatment between the two groups, indicating that the monthly frequency, severity, duration, and disability for headaches were not significantly different between the groups.   of migraine (21,27). Association between low serum levels of vitamin D 3 and more incidence of chronic headaches, and the effectiveness of vitamin D 3 in the treatment of a few headache disorders are reported (7,17,28,29).
Some studies reported that the incidence of migraine attacks increases during autumn and winter in children, or a seasonal change in vitamin D 3 level is correlated with an increase in migraine attacks, which mostly occurs in winter (17,21,30).
In the present study, the efficacy and safety of topiramate plus vitamin D 3 and topiramate alone  (21).
The limitations of the present study were lack of placebo, short duration of treatment, and lack of follow-up after discontinuation.

In Conclusion
Results of the current study showed that the combination of topiramate and vitamin D 3 was more effective than topiramate alone in the reduction of monthly frequency and the disability score of migraine in children, and vitamin D 3 therapy might be considered a safe and effective strategy for the prophylaxis of pediatric migraine. Further clinical trials with larger sample sizes, altitude control, and seasonal differences are required to determine the optimal dose of vitamin D 3 for the prevention of pediatric migraine.

Acknowledgment
This study was funded by a grant from the Deputy

Conflicts of interest
The researchers received no financial support from any pharmaceutical companies. The authors declared no conflicts of interest.